Accumulating evidence from man and experimental animals suggests that podocyte depletion is a major mechanism underlying the development of glomerulosclerosis. This appears to be true for diabetes, hypertension, FSGS and other gtomerular diseases that account for 80% of ESRD. ESRD as a result of these conditions costs well in excess of $10 billion per year in the US. If this hypothesis is correct it will provide a rational target for therapeutic direction and monitoring of progression of renal failure. Thus the stakes are high to determine whether or not this hypothesis is correct. In this application we set out to test this hypothesis using the cleanest method that we can devise. We will use a transgenic strategy based on our preliminary work to identify a podocyte-specific promotor (podocin) and develop a mouse that expresses the Cre-recombinase enzyme only in podocytes. We will use these systems to deliver a cytotoxic signal (diptheria toxin-A or DT-A) to podocytes using three different approaches. We will express the human DT-A receptor (HB-EGFR) on the surface of podocytes and use injected DT-A to target podocytes for cell death. This approach makes use of the fact that the mouse homologue does not bind DT-A with high affinity and explains why mice are not susceptible to C. diphtheria. The second strategy will use expression of DT-A in podocytes under the control of an inducible promotor. The third strategy will make use of lines of mice in which there is mosaicism for Cre expression in podocytes. These mice will be targeted to express DT-A directly in some but not all podocytes in order to obtain graded killing of podocytes. These three approaches are mutually complementary and wilt provide model systems in which the central hypothesis can be tested and which can be provided to other investigators working in the areas of diabetes, hypertension, FSGS and other forms of progressive glomerular diseases.